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British pharmaceutical giant GlaxoSmithKline (GSK) is being investigated by Chinese health authorities amid allegations that the company's seven-year-old research and development center in Shanghai may have suppressed animal studies of an experimental monoclonal antibody treatment for multiple sclerosis (MS) before launching human trials of the drug.

The issue arose after the New York Times obtained an internal GSK audit, conducted in 2011, that cited “critical bioethics problems with data reporting” including problems with phase 1 animal studies of ozanezumab. The document said researchers failed to report data from six studies in mice before starting human trials in MS patients and those with amyotrophic lateral sclerosis (ALS).

According to the July 23 story, the company halted human trials of ozanezumab for MS after the omitted mouse data was brought to the attention of the center's administrator. Nonetheless, the company has continued to test the drug in ALS patients in several countries, but not in the United States.

On July 30, China's Center for Drug Evaluation launched an investigation on the center's data reporting practices and other issues.

GSK spokeswoman Melinda Stubbee told Neurology Today that the company's audit did not identify any undisclosed data relating to the use of ozanezumab in ALS and the pre-clinical data supported investigation in human subjects. Moreover, none of the preclincial ALS studies were conducted in China.

“The audit determined that there needed to be more rigorous processes implemented to ensure the information from pre-clinical trials is shared and recorded in a consistent way. The documentation issues were not intentionalβ and patient safety was not compromised.”

The excluded studies in mice also supported progressing to human studies and did not point to any risk of toxicity or other safety concerns, she said, but “when the full range of data from all of the studies was reviewed, GSK determined that the efficacy would not be strong enough to continue the trial in multiple sclerosis and it was terminated.”

AN ETHICAL LAPSE

Arthur Caplan, PhD, professor of bioethics and director of the Division of Medical Ethics at New York University Langone Medical Center, said proceeding into human trials before all animal data are considered is “a mortal sin.”

He told Neurology Today in a telephone interview that the issue applies not just to GSK, but to all pharmaceutical companies with operations in China and other emerging countries.

“I believe this is an emerging trend. China is a potentially huge market and a very attractive environment for research, and I think every other major drug company wants to be there too. But Glaxo has hit an ethical rock this time, and they got burned.”

Well-established research protocols and clinical trial oversight is a relatively new concept for researchers in such emerging countries, and better training and auditing processes are needed to avoid such problems.

“I do not think these problems are insolvable, but this specific incident is very serious and a lesson — in capital letters — for other drug companies conducting clinical trials and research in China and other emerging countries,” he told Neurology Today.

It is not yet publically known whether the excluded animal data was unfavorable or simply a reporting error by researchers, he noted.

“Until these data are available to all of us, I believe all human trials of this drug should stop, and because of this uncertainty, I do not think we can trust any findings about ozanezumab. But it also puts other clinical trials from China under suspicion, and this makes me very nervous.”

IOM: GLOBAL STRATEGIES NEEDED

On Aug. 1, the Institute of Medicine (IOM) released a report concluding that there are a number of steps that could help “harmonize” regulation of drug development around the world, especially in emerging markets where problems like the ones in Shanghai might occur.

Based on a workshop earlier this year, the report said many low- and middle-income developing countries “lack the regulatory capacity for drug approval,” while differences in regulatory requirements among countries can cause delays in new drug approvals and even necessitate additional clinical trials.

More consistent standards could improve the efficiency and clarity of drug development and evaluation and, ultimately, “promote and enhance product quality and the public health,” according to the report. “The FDA cannot do its job well without substantive improvements in the capacity of its counterpart agencies in emerging economies, especially the sharing of inspection reports.”

Eric Campbell, PhD, professor of medicine at Harvard Medical School, said the ozanezumab controversy points to the need for closer scrutiny of data from trials conducted in emerging countries.

“This is a classic example of how clinical trials can go wrong in the absence of strict regulatory oversight,” he told Neurology Today in a telephone interview.

“Unlike in many developing countries, in the US, we have a large regulatory structure in place for conducting and overseeing clinical trials, and when there are problems there is a quick response to protect clinical trial subjects,” he said. “In China, and in many other emerging countries where large pharmaceutical companies are conducting studies, the systems of oversight are are less advanced and, without a sound regulatory infrastructure, there is always the risk of something going wrong without it being reported or detected.”

Dr. Campbell is also director of research at the Mongan Institute for Health Policy at Massachusetts General Hospital.

“The problems with the ozanezumab studies are not unique to GSK,” he noted. “Many large pharmaceutical companies are moving trials overseas.”

Countries where the overhead cost of conducting trials is significantly lower, and where there is less oversight, are becoming increasingly attractive for major drug companies, and these companies are driven, above all, by the bottom line, Dr. Campell said.

“Big drug companies are no different from major oil, defense, or financial corporations, so it is important for all of us to maintain a healthy skepticism of any clinical trial where the work has been done in an emerging country. Without the type of regulatory infrastructure we have here in the US, it is impossible to know if a trial has been conducted with the same degree of oversight, or if results are being reported accurately.”

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